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ABSTRACT: Glucose-induced insulin secretion from pancreatic ß-cells depends critically on activity of ATP-sensitive K+ channels (KATP channel). We previously generated mice lacking Kir6.2, the pore subunit of the ß-cell KATP channel (Kir6.2-/-), that show almost no insulin secretion in response to glucose in vitro. In the present study, we compared insulin secretion by voluntary feeding (self-motivated, oral nutrient ingestion) and by forced feeding (intra-gastric nutrient injection via gavage) in wild-type (Kir6.2+/+) and Kir6.2-/- mice. Under ad libitum feeding or during voluntary feeding of standard chow, blood glucose levels and plasma insulin levels were similar in Kir6.2+/+ and Kir6.2-/- mice. By voluntary feeding of carbohydrate alone, insulin secretion was induced significantly in Kir6.2-/- mice, but was markedly attenuated compared to that in Kir6.2+/+ mice. On forced feeding of standard chow or carbohydrate alone, the insulin secretory response was markedly impaired or completely absent in Kir6.2-/- mice. Pre-treatment of a muscarine receptor antagonist, atropine methyl nitrate, which does not cross the blood-brain barrier, almost completely blocked insulin secretion induced by voluntary feeding of standard chow or carbohydrate in Kir6.2-/- mice. Substantial glucose-induced insulin secretion was induced in pancreas perfusion study of Kir6.2-/- mice only in the presence of carbamylcholine. These results suggest that a KATP channel-independent mechanism mediated by the vagal nerve plays a critical role in insulin secretion in response to nutrients in vivo.
Journal of Endocrinology 04/2013; · 3.55 Impact Factor
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ABSTRACT: Although various formulas predicting plasma sodium level ([Na]) are proposed for correction of hyponatremia, it seems that an anticipated [Na] frequently exceeds or falls below the measured [Na], especially in syndrome of inappropriate antidiuretic hormone secretion (SIADH). The causative factors of the fluctuation have never been investigated clearly. The aim of this study was to identify the determining factors for accurate prediction of [Na] by comparing data from previously proposed formulas and a novel osmotic compartment model (O-C model). The O-C model, which simulates the amounts of osmoles in extracellular and intracellular fluids, can estimate resultant osmotic water shift (OWS) and [Na]. The accuracy of representative formulas was verified in a point-to-point study using blood and urine samples obtained every 4 hours from 9 patients. Among 161 measurement points, a large fluctuation of urine volume and urine sodium level was observed. The gap between anticipated and measured [Na] in the widely used Adrogue-Madias formula was -0.5 ± 0.1 mEq/L/4 h (mean ± standard error), showing a marked tendency to underestimate [Na]. The gap in the O-C model including OWS was 0.1 ± 0.1 mEq/L/4 h, and that eliminating OWS was 1.9 ± 0.2 mEq/L/4 h, indicating that measurement of urine output and estimation of resulting OWS are essential for a superior prediction of [Na] in SIADH. A simulation study with the O-C model including OWS unveiled a distinctive correction pattern of [Na] dependent on the urine volume and urine sodium level, providing a useful choice for the proper type and rate of infusion.
Translational research : the journal of laboratory and clinical medicine. 04/2013;
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Endocrine 02/2013; · 1.42 Impact Factor
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Diabetes care 02/2013; 36(2):e22. · 8.09 Impact Factor
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ABSTRACT: OBJECTIVE: Alpha-glucosidase inhibitors (α-GIs) show various anti-diabetic or anti-obesity effects in addition to the suppression of postprandial hyperglycemia. Based on recent observations that bile acids (BAs) are involved in glucose and energy homeostasis, we examined the ability of miglitol, an α-GI, to influence BA metabolism and ameliorate insulin resistance and obesity. MATERIALS/METHODS: NSY mice, representing an obese type 2 diabetic model, were fed with a high-fat diet and treated with miglitol for 4 or 12weeks. BAs were quantified in feces, blood from the portal vein or the vena cava and in the liver. The gene expression of type 2 iodothyronine deiodinase (D2) in brown adipose tissues, gluconeogenetic enzymes in the liver and adipokines in epididymal fat was measured, and portal blood glucagon-like peptide-1 (GLP-1) levels, body weight changes, glucose tolerance along with insulin sensitivity were evaluated. RESULTS: Miglitol significantly increased BAs in both feces and portal blood while the hepatic BA level was reduced. The drug clearly enhanced active GLP-1 secretion into the portal blood and there was a good positive correlation between the active GLP-1 levels and portal blood BA concentrations. D2 expression in brown adipose tended to increase in association with the elevated BA concentrations. Miglitol ameliorated body weight gain, glucose intolerance, insulin resistance and inflammatory adipokine upregulation that were induced by a high-fat diet. CONCLUSIONS: Collectively, miglitol substantially affects BA regulation in mice and this novel finding may explain in part the known favourable effects of the drug on diabetes and obesity.
Metabolism: clinical and experimental 11/2012; · 2.59 Impact Factor
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Ayako Fukami,
Yusuke Seino,
Nobuaki Ozaki,
Michiyo Yamamoto,
Chisato Sugiyama,
Eriko Sakamoto-Miura,
Tatsuhito Himeno,
Yoshiko Takagishi,
Shin Tsunekawa,
Safina Ali,
Daniel J Drucker,
Yoshiharu Murata,
Yutaka Seino, Yutaka Oiso,
Yoshitaka Hayashi
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ABSTRACT: Glucagon and glucagon-like peptide-1 (GLP-1) are produced in pancreatic α-cells and enteroendocrine L-cells, respectively, in a tissue-specific manner from the same precursor, proglucagon, that is encoded by glucagon gene (Gcg), and play critical roles in glucose homeostasis. Here, we studied glucose homeostasis and β-cell function of Gcg-deficient mice that are homozygous for a Gcg-GFP knock-in allele (Gcg(gfp/gfp)). The Gcg(gfp/gfp) mice displayed improved glucose tolerance and enhanced insulin secretion, as assessed by both oral glucose tolerance test (OGTT) and intraperitoneal glucose tolerance test (IPGTT). Responses of glucose-dependent insulinotropic polypeptide (GIP) to both oral and intraperitoneal glucose loads were unexpectedly enhanced in Gcg(gfp/gfp) mice, and immunohistochemistry localized GIP to pancreatic β-cells of Gcg(gfp/gfp) mice. Furthermore, secretion of GIP in response to glucose was detected in isolated islets of Gcg(gfp/gfp) mice. Blockade of GIP action in vitro and in vivo by cAMP antagonism and genetic deletion of the GIP receptor, respectively, almost completely abrogated enhanced insulin secretion in Gcg(gfp/gfp) mice. These results indicate that ectopic GIP expression in β-cells maintains insulin secretion in the absence of proglucagon-derived peptides (PGDPs), revealing a novel compensatory mechanism for sustaining incretin hormone action in islets.
Diabetes 10/2012; · 8.29 Impact Factor
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Tetsuji Okawa,
Hideki Kamiya,
Tatsuhito Himeno,
Jiro Kato,
Yusuke Seino,
Atsushi Fujiya,
Masaki Kondo,
Shin Tsunekawa,
Keiko Naruse,
Yoji Hamada,
Nobuaki Ozaki,
Zhao Cheng,
Tetsutaro Kito,
Hirohiko Suzuki,
Sachiko Ito, Yutaka Oiso,
Jiro Nakamura,
Ken-Ichi Isobe
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ABSTRACT: Impaired vascularity and nerve degeneration are the most important pathophysiological abnormalities of diabetic polyneuropathy (DPN). Therefore, regeneration of both vascular and nervous systems is required for the treatment of DPN. The neural crest (NC) is a transient embryonic structure in vertebrates that differentiates into a vast range of cells, including peripheral neurons, Schwann cells and vascular smooth muscle cells. In this study, we investigated the ability of transplantation of NC like (NCL) cells derived from aged mouse induced pluripotent stem (iPS) cells in the treatment of DPN. iPS cells were induced to differentiate into neural cells by stromal cell-derived inducing activity (SDIA) and subsequently supplemented with bone morphogenetic protein 4 to promote a differentiation of NC lineage. After the induction, p75 neurotrophin receptor positive NCL cells were purified using magnetic-activated cell sorting. Sorted NCL cells differentiated to peripheral neurons, glial cells and smooth muscle cells by additional SDIA. NCL cells were transplanted into hind limb skeletal muscles of 16-week streptozotocin-diabetic mice. Nerve conduction velocity, current perception threshold, intraepidermal nerve fiber density, sensitivity to thermal stimuli, sciatic nerve blood flow, plantar skin blood flow and capillary number-to-muscle fiber ratio were evaluated. Four-weeks after the transplantation, transplanted cells engrafted with producing growth factors; nerve growth factor, neurotrophin 3, vascular endothelial growth factor and basic fibroblast growth factor. It was also confirmed that some engrafted cells differentiated into vascular smooth muscle cells or Schwann cell like cells at each intrinsic site. The transplantation improved the impaired nerve and vascular functions. These results suggest that transplantation of NCL cells derived from iPS cells could have therapeutic effects on DPN through paracrine actions of growth factors and differentiation into Schwann cell like cells and vascular smooth muscle cells.
Cell Transplantation 10/2012; · 5.13 Impact Factor
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ABSTRACT: The area postrema (AP) is a circumventricular organ that lacks a blood-brain barrier. Previous studies have shown that the lesion of AP (APX) attenuated hyperphagic responses to glucoprivation. As the orexigenic neuropeptide Y (NPY) neurons have been implicated in the regulation of food intake, we examined whether the activation of NPY neurons by glucoprivation is mediated through the AP as well. In agreement with previous studies, hyperphagic responses to an injection of 2-deoxy-D-glucose that blocks glucose utilization were significantly attenuated in the APX group compared with the sham-operated (Sham) group. However, the expression levels of NPY heteronuclear RNA, a sensitive indicator for the gene transcription, were significantly increased in the arcuate nucleus by a 2-deoxy-D-glucose injection in both the APX and the Sham groups, and there were no significant differences in the values between groups. These data suggest that the hyperphagic response to glucoprivation, but not the activation of NPY gene transcription in the arcuate nucleus, was mediated through the AP in the hindbrain.
Neuroreport 05/2012; 23(11):673-5. · 1.66 Impact Factor
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ABSTRACT: In this study we aimed to identify the physiological roles of G protein-coupled receptor 84 (GPR84) in adipose tissue, together with medium-chain fatty acids (MCFAs), the specific ligands for GPR84. In mice, high-fat diet up-regulated GPR84 expression in fat pads. In 3T3-L1 adipocytes, co-culture with a macrophage cell line, RAW264, or TNFα remarkably enhanced GPR84 expression. In the presence of TNFα, MCFAs down-regulated adiponectin mRNA expression in 3T3-L1 adipocytes. Taken together, our results suggest that GPR84 emerges in adipocytes in response to TNFα from infiltrating macrophages and exacerbates the vicious cycle between adiposity and diabesity.
FEBS letters 02/2012; 586(4):368-72. · 3.54 Impact Factor
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ABSTRACT: The immunoglobulin heavy chain binding protein (BiP) is an endoplasmic reticulum (ER) chaperone that facilitates the proper folding of newly synthesized secretory and transmembrane proteins. Here we report that BiP mRNA was expressed in the supraoptic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus in wild-type mice under basal conditions. Dual in situ hybridization in the SON and PVN demonstrated that BiP mRNA was expressed in almost all the neurons of arginine vasopressin (AVP), an antidiuretic hormone. BiP mRNA expression levels were increased in proportion to AVP mRNA expression in the SON and PVN under dehydration. These data suggest that BiP is involved in the homeostasis of ER function in the AVP neurons in the SON and PVN.
Peptides 02/2012; 33(2):346-50. · 2.43 Impact Factor
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Endocrine 02/2012; 41(1):160-1. · 1.42 Impact Factor
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Diabetes research and clinical practice 01/2012; 96(3):e55-6. · 2.16 Impact Factor
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Chika Watanabe,
Yusuke Seino,
Hiroki Miyahira,
Michiyo Yamamoto,
Ayako Fukami,
Nobuaki Ozaki,
Yoshiko Takagishi,
Jun Sato,
Tsutomu Fukuwatari,
Katsumi Shibata, Yutaka Oiso,
Yoshiharu Murata,
Yoshitaka Hayashi
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ABSTRACT: Glucagon is believed to be one of the most important peptides for upregulating blood glucose levels. However, homozygous glucagon-green fluorescent protein (gfp) knock-in mice (Gcg(gfp/gfp): GCGKO) are normoglycemic despite the absence of proglucagon-derived peptides, including glucagon. To characterize metabolism in the GCGKO mice, we analyzed gene expression and metabolome in the liver. The expression of genes encoding rate-limiting enzymes for gluconeogenesis was only marginally altered. On the other hand, genes encoding enzymes involved in conversion of amino acids to metabolites available for the tricarboxylic acid cycle and/or gluconeogenesis showed lower expression in the GCGKO liver. The expression of genes involved in the metabolism of fatty acids and nicotinamide was also altered. Concentrations of the metabolites in the GCGKO liver were altered in manners concordant with alteration in the gene expression patterns, and the plasma concentrations of amino acids were elevated in the GCGKO mice. The insulin concentration in serum and phosphorylation of Akt protein kinase in liver were reduced in GCGKO mice. These results indicated that proglucagon-derived peptides should play important roles in regulating various metabolic pathways, especially that of amino acids. Serum insulin concentration is lowered to compensate the impacts of absent proglucagon-derived peptide on glucose metabolism. On the other hand, impacts on other metabolic pathways are only partially compensated by reduced insulin action.
Diabetes 01/2012; 61(1):74-84. · 8.29 Impact Factor
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ABSTRACT: A 47-year-old woman presented with hypokalemia (2.4 mmol/L). She also had hypomagnesemia, hypocalciuria, and hyperreninemic hyperaldosteronism. Sequence analysis revealed a compound heterozygous mutation, R655C and R955Q, in the SLC12A3 gene. These findings were compatible with Gitelman's syndrome (GS). Eplerenone, a selective aldosterone blocker, in combination with oral potassium chloride improved serum potassium level (3.6 mmol/L) with no apparent adverse effect. Although eplerenone has an advantage over spironolactone for its selective affinity for the aldosterone receptor, the efficacy and safety of eplerenone for GS is little understood. Our observation suggests that eplerenone is a useful treatment option for GS.
Internal Medicine 01/2012; 51(1):83-6. · 0.94 Impact Factor
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ABSTRACT: BACKGROUND/AIMS: Although contrast-induced acute kidney injury (CIAKI) is a major complication associated with angiography, the prophylaxis is not well established. Use of a low dose of carperitide for preventing CIAKI remains controversial. We examined the protective effect of carperitide on CIAKI after coronary angiography with a small contrast volume in chronic kidney disease (CKD) patients with coronary artery disease. METHODS: We randomly assigned 112 consecutive patients to a carperitide or a control group. The contrast volume was kept under 150 ml. The primary endpoint was the incidence of CIAKI defined by a serum creatinine of ≥25% or a serum creatinine of ≥0.5 mg/dl from baseline within 48 h. The secondary endpoint was a change in renal function at 1 week after the procedure. Results: The baseline characteristics and contrast volumes (carperitide group: 67.4 ± 38.2 ml vs. control group: 64.8 ± 20.5 ml, p = 0.661) were comparable in the two groups. The incidence of CIAKI was similar in the two groups (carperitide group: 8.5% vs. control group: 5.7%, p = 0.564). A multivariate analysis revealed that a hypotension ≥20 mm Hg was a significant predictor of developing CIAKI in the carperitide group (p = 0.015). The incidence of CIAKI in the carperitide group without hypotension was rare, but not significantly different (carperitide group: 2.4% vs. control group: 5.7%, p = 0.432). Conclusions: This study indicated that the use of a small contrast volume suppressed the incidence of CIAKI and that carperitide had no prophylactic effect against CIAKI. Our results also revealed the impact of hypotension on the development of CIAKI in the carperitide group.
Nephron extra. 01/2012; 2(1):303-10.
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Internal Medicine 01/2012; 51(22):3223-4. · 0.94 Impact Factor
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ABSTRACT: In obesity, levels of tumor necrosis-factor α (TNFα) are well known to be elevated in adipose tissues or serum, and a high-fat diet (HFD) reportedly increases TNFα expression in the hypothalamus. The expression levels of hypothalamic protein tyrosine phosphatase 1B (PTP1B), a negative regulator of leptin and insulin signaling, are also elevated by HFD, and several lines of evidence support a relationship between TNFα and PTP1B. It remains unclear however how TNFα acts locally in the hypothalamus to regulate hypothalamic PTP1B expression and activity. In this study, we examined whether TNFα can regulate PTP1B expression and activity using rat hypothalamic organotypic cultures. Incubation of cultures with TNFα resulted in increases in mRNA expression, protein levels and activity of PTP1B in a dose- and time-dependent manner, respectively compared with controls. TNFα-induced PTP1B protein levels were not influenced by co-incubation with the sodium channel blocker tetrodotoxin, indicating that the action of TNFα is independent of action potentials. TNFα also increased phosphorylation of p65, a subunit of nuclear factor-κB (NFκB), in a dose- and time-dependent manner. While incubation with inhibitors of NFκB did not affect basal levels of either p65 phosphorylation or PTP1B expression, it markedly suppressed both TNFα-induced p65 phosphorylation and PTP1B expression to almost basal levels. These data suggest that TNFα acts on the hypothalamus to increase hypothalamic PTP1B expression and activity via the NFκB pathway, and that TNFα-mediated induction of NFκB in the hypothalamus may cause leptin and insulin resistance in the hypothalamus by increasing hypothalamic PTP1B activity.
Regulatory Peptides 12/2011; 174(1-3):58-64. · 2.11 Impact Factor
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Yoshiaki Morishita,
Hiroshi Arima,
Maiko Hiroi,
Masayuki Hayashi,
Daisuke Hagiwara,
Naoya Asai,
Nobuaki Ozaki,
Yoshihisa Sugimura,
Hiroshi Nagasaki,
Akira Shiota,
Masahide Takahashi, Yutaka Oiso
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ABSTRACT: Familial neurohypophysial diabetes insipidus (FNDI) is caused by mutations in the gene locus of arginine vasopressin (AVP), an antidiuretic hormone. Although the carriers are normal at birth, polyuria and polydipsia appear several months or years later. Previously, we made mice possessing a mutation causing FNDI and reported that the mice manifested progressive polyuria as do the patients with FNDI. Here, we report that decreases in AVP mRNA expression in the supraoptic nucleus were accompanied by shortening of the AVP mRNA poly(A) tail length in the FNDI mice, a case in which aggregates accumulated in the endoplasmic reticulum (ER) of the hypothalamic AVP neurons. Expression levels of AVP heteronuclear RNA in the supraoptic nucleus, a sensitive indicator for gene transcription, were not significantly different between FNDI and wild-type mice. Incubation of hypothalamic explants of wild-type mice with ER stressors (thapsigargin and tunicamycin) caused shortening of the poly(A) tail length of AVP and oxytocin mRNA, accompanied by decreases in their expression. On the other hand, an ER stress-reducing molecule (tauroursodeoxycholate) increased the poly(A) tail length as well as the expression levels of AVP and oxytocin mRNA. These data reveal a novel mechanism by which ER stress decreases poly(A) tail length of neurohypophysial hormones, probably to reduce the load of unfolded proteins.
Endocrinology 12/2011; 152(12):4846-55. · 4.46 Impact Factor
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Hidetaka Suga,
Taisuke Kadoshima,
Maki Minaguchi,
Masatoshi Ohgushi,
Mika Soen,
Tokushige Nakano,
Nozomu Takata,
Takafumi Wataya,
Keiko Muguruma,
Hiroyuki Miyoshi,
Shigenobu Yonemura, Yutaka Oiso,
Yoshiki Sasai
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ABSTRACT: The adenohypophysis (anterior pituitary) is a major centre for systemic hormones. At present, no efficient stem-cell culture for its generation is available, partly because of insufficient knowledge about how the pituitary primordium (Rathke's pouch) is induced in the embryonic head ectoderm. Here we report efficient self-formation of three-dimensional adenohypophysis tissues in an aggregate culture of mouse embryonic stem (ES) cells. ES cells were stimulated to differentiate into non-neural head ectoderm and hypothalamic neuroectoderm in adjacent layers within the aggregate, and treated with hedgehog signalling. Self-organization of Rathke's-pouch-like three-dimensional structures occurred at the interface of these two epithelia, as seen in vivo, and various endocrine cells including corticotrophs and somatotrophs were subsequently produced. The corticotrophs efficiently secreted adrenocorticotropic hormone in response to corticotrophin releasing hormone and, when grafted in vivo, these cells rescued the systemic glucocorticoid level in hypopituitary mice. Thus, functional anterior pituitary tissue self-forms in ES cell culture, recapitulating local tissue interactions.
Nature 11/2011; 480(7375):57-62. · 36.28 Impact Factor
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Enyu Imai,
Yoshinari Yasuda,
Masaru Horio,
Kanako Shibata,
Sawako Kato,
Yu Mizutani,
Junko Imai,
Mutsuharu Hayashi,
Hideki Kamiya, Yutaka Oiso,
Toyoaki Murohara,
Shoichi Maruyama,
Seiichi Matsuo
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ABSTRACT: Measuring sodium excretion in a 24-h urine collection is the most reliable method of estimating salt intake, but it is not applicable to all patients. As an alternative, equations for estimating Na excretion from Japanese by a spot urine sample were created, but they have not been validated in patients with chronic kidney disease (CKD), which are frequently associated with nocturia and medication.
We enrolled 136 patients with CKD and collected both 24-h urine and the first morning urine. Na excretion was estimated from the first morning urine by Kawasaki's equation, which was originally used for the second morning urine, and Tanaka's equation, which is applied for spot urine samples taken at any time from 9 am to 7 pm. We evaluated the two equations for bias, RMSE and accuracy within 30 and 50% of the measured Na excretion.
Bias, RMSE and accuracy within 30% of the estimated Na excretion were 48 ± 69 and 2 ± 69 mmol/day, 84 and 69 mmol/day, and 35 and 49% using Kawasaki's equation and Tanaka's equation, respectively. Na excretion in the first morning urine was accurately estimated by Tanaka's equation, but it was overestimated by Kawasaki's equation. Nocturia and medication such as diuretics and ACE inhibitor or angiotensin receptor blocker did not affect the accuracy with which Na excretion was estimated by Tanaka's equation substantially.
Tanaka's equation for estimating Na excretion from the first morning urine in patients with CKD is accurate enough for use in clinical practice.
Clinical and Experimental Nephrology 09/2011; 15(6):861-7. · 1.37 Impact Factor
